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Synera

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Synera

CLINICAL PHARMACOLOGY

Mechanism Of Action

SYNERA applied to intact skin provides local dermal analgesia by the release of lidocaine and tetracaine from the patch into the skin. Lidocaine is an amide-type local anesthetic agent and tetracaine is an ester-type local anesthetic agent. Both lidocaine and tetracaine block sodium ion channels required for the initiation and conduction of neuronal impulses, resulting in local anesthesia.

Pharmacokinetics

Absorption

Application of one SYNERA patch for 30 minutes in adults produced peak plasma concentrations of lidocaine less than 5 ng/mL while plasma levels of tetracaine were below the limit of quantitation ( < 0.9 ng/mL) in all subjects tested (n = 12, see Table 1). SYNERA application up to 60 minutes did not significantly increase plasma levels of lidocaine or tetracaine compared to a 30-minute application.

Table 1 : Absorption of Lidocaine and Tetracaine from SYNERA in Normal Adult Volunteers (n = 12)

Number of SYNERA Patches Age Range (yr) Application Time (min) Drug Content (mg) Estimated Amount Absorbed (mg)* Cmax (ng/mL) Tmax (hr)
1 18-65 30 Lidocaine, 70 1.7 1.7 1.7
Tetracaine, 70 1.6 <0.9 na
* Estimated absorbed dose was calculated by subtracting the residual amount of drug in each patch from the labeled claim
na = not applicable
The surface area of application was 10 cm² per SYNERA patch.

Application of SYNERA to broken or inflamed skin or more than four simultaneous or sequentially applied SYNERA patches could result in higher plasma levels of local anesthetic that carries the risk of systemic toxicity.

Simultaneous or sequential application of multiple SYNERA patches is not recommended. However, plasma levels of lidocaine and tetracaine have been determined in clinical pharmacology studies following multiple successive and simultaneous applications of SYNERA patches on intact skin. Maximum plasma levels of lidocaine after the application of a) four successive SYNERA patches for 30 minutes each with a 30-minute interval between each patch application, and b) three SYNERA patches for 60 minutes each with a 60-minute interval between each application were less than 12 ng/mL and 8 ng/mL, respectively. Tetracaine was not detected in plasma following either treatment. Simultaneous application of two or four SYNERA patches for 60 minutes produced peak plasma concentrations of lidocaine of less than 9 ng/mL, while tetracaine plasma concentrations were not detectable in all subjects (n=22). Sequential 30-minute applications of four SYNERA patches at 60-minute intervals produced peak plasma concentrations of lidocaine of less than 12 ng/mL, while tetracaine plasma concentrations were below the limit of quantitation (n=11).

Distribution

When lidocaine is administered intravenously to healthy volunteers, the steady-state volume of distribution is approximately 0.8 to 1.3 L/kg. At lidocaine concentrations observed following the recommended product application, approximately 75% of lidocaine is bound to plasma proteins, primarily alpha-1-acid glycoprotein. At much higher plasma concentrations (1 to 4 mcg/mL of free base) the plasma protein binding of lidocaine is concentration dependent. Lidocaine crosses the placental and blood brain barriers, presumably by passive diffusion. CNS toxicity is seen with plasma levels of 5000 ng/mL of lidocaine; however a small number of patients reportedly may show signs of toxicity at approximately 1000 ng/mL. Volume of distribution and protein binding have not been determined for tetracaine due to rapid hydrolysis in plasma.

Metabolism

It is not known if lidocaine or tetracaine is metabolized in the skin. Lidocaine is metabolized rapidly by the liver to a number of metabolites including monoethylglycinexylidide (MEGX) and glycinexylidide (GX), both of which have pharmacologic activity similar to, but less potent than that of lidocaine. The major metabolic pathway of lidocaine, sequential N-deethylation to monoethylglycinexylidide (MEGX) and glycinexylidide (GX), is primarily mediated by CYP1A2 with a minor role of CYP3A4. The metabolite, 2,6-xylidine, has unknown pharmacologic activity. Following intravenous administration of lidocaine, MEGX and GX concentrations in serum range from 11% to 36% and from 5% to 11% of lidocaine concentrations, respectively. Serum concentrations of MEGX were about one-third the serum lidocaine concentrations. Tetracaine undergoes rapid hydrolysis by plasma esterases. Primary metabolites of tetracaine include para-aminobenzoic acid and diethylaminoethanol, both of which have an unspecified activity.

Elimination

The half-life of lidocaine elimination from the plasma following intravenous administration is approximately 1.8 hr. Lidocaine and its metabolites are excreted by the kidneys. More than 98% of an absorbed dose of lidocaine can be recovered in the urine as metabolites or parent drug. Less than 10% of lidocaine is excreted unchanged in adults, and approximately 20% is excreted unchanged in neonates. The systemic clearance is approximately 8-10 mL/min/kg. During intravenous studies, the elimination half-life of lidocaine was statistically significantly longer in elderly patients (2.5 hours) than in younger patients (1.5 hours). The half-life and clearance for tetracaine have not been established for humans, but hydrolysis in the plasma is rapid.

Pediatric Patients

Application of one SYNERA patch for up to 30 minutes in children 4 months to 12 years of age (n=18) produced maximum peak plasma concentrations of lidocaine and tetracaine of 63 ng/mL and 65 ng/mL, respectively. Application of two SYNERA patches for up to 30 minutes to children 4 months to 12 years of age (n=19) produced peak lidocaine levels of up to 331 ng/mL and tetracaine levels of less than 5 ng/mL.

Elderly

After application of one SYNERA patch for 20 minutes, plasma levels of lidocaine and tetracaine were not detectable in elderly subjects (> 65 years of age, mean 72.0 ±4.3 years, n=10). After simultaneous application of two SYNERA patches for 60 minutes to elderly subjects (> 65 years of age, mean 69.5 ±3.7 years, n=12), the maximum peak lidocaine concentration was 6 ng/mL and tetracaine was not detectable. During intravenous studies, the elimination half-life of lidocaine was statistically significantly longer in elderly patients (2.5 hours) than in younger patients (1.5 hours).

Cardiac, Renal and Hepatic Impairment

No specific pharmacokinetic studies were conducted. The half-life of lidocaine may be increased in individuals with cardiac or hepatic dysfunction. There is no established half-life for tetracaine due to rapid hydrolysis in the plasma.

Clinical Studies

Superficial Venous Access

Three randomized, double-blind, placebo controlled clinical trials in adult and geriatric subjects evaluated the degree of dermal analgesia upon venipuncture following a 20-minute treatment with SYNERA or a placebo patch (patch with heating component but no drug). In each trial, subjects received SYNERA on one arm and placebo patch on the other. In all three studies pain was measured by a 100-mm VAS in which a lower VAS score corresponds to less pain. In the first study in 21 subjects, median VAS scores for SYNERA and placebo treatments were 1 mm and 9 mm, respectively. In the second study in 40 subjects, median VAS scores were 5 mm and 28 mm for SYNERA and placebo treatments, respectively. In the third study, in 40 subjects over the age of 65 years, median VAS scores for SYNERA and placebo treatments were 8 mm and 14 mm, respectively.

In a randomized, double-blind, placebo controlled study, 61 pediatric patients received either SYNERA or placebo for 20 minutes prior to venipuncture or IV cannulation in the antecubital fossa or dorsum of the hand. Subjects were stratified by age group (3 to 6 years and 7 to 17 years). Children in the younger group reported less pain on IV cannulation with SYNERA than with placebo, as rated using a six-point Oucher pain scale with faces. Children in the older group rated their pain using an eleven-point Oucher pain scale that contained both faces and numbers. Pain scores on IV cannulation in the older children treated with SYNERA were not significantly different from pain scores in those treated with placebo.

In a double-blind trial in 250 adults, subjects were randomized to receive either SYNERA without heating element or SYNERA with heating element, prior to venipuncture. Median VAS scores for the patch with the heating element and without the heating element were 17 mm and 22 mm, respectively.

Superficial Dermatological Procedures

In one randomized, double-blind, placebo controlled study, 94 adult subjects received either SYNERA or placebo patch for 30 minutes prior to a superficial dermatological procedure such as superficial excision, shave biopsy or electrodessication. Median VAS scores for SYNERA and placebo treatments were 5 mm and 31 mm, respectively. In a similarly designed study in 74 subjects over the age of 65 years, less pain was reported following SYNERA treatment compared to placebo with median VAS scores for SYNERA and placebo treatments of 10 mm and 23 mm, respectively.

In a randomized, double-blind, placebo controlled study, 88 pediatric patients were stratified by age group (3 to 6 years and 7 to 17 years) to receive a 30-minute application of either SYNERA or placebo patch, prior to lidocaine injection. In younger children who used the Oucher pain scale with faces, those receiving SYNERA reported less pain from lidocaine injection than those receiving placebo. Older children used the numerical Oucher pain scale to report pain intensity. There was no difference between treatments observed in the older children.

Last reviewed on RxList: 3/28/2014
This monograph has been modified to include the generic and brand name in many instances.

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